In vivo effects of peroxovanadium compounds in BB rats

  • J. F. Yale
  • C. Vigeant
  • C. Nardolillo
  • Q. Chu
  • J.-Z. Yu
  • A. Shaver
  • B. L. Posner
Part of the Developments in Molecular and Cellular Biochemistry book series (DMCB, volume 16)


Peroxovanadium compounds, each containing an oxo ligand, one or two peroxo anions, and an ancillary ligand in the inner coordination sphere of vanadium, were synthesized, crystallized and characterized by 51V NMR as > 95% pure. They markedly decreased plasma glucose in insulin-deprived diabetic BB rats, with a nadir occurring between 60 and 100 min after intravenous, intraperitoneal or subcutaneous administration. Plasma glucose was reduced after oral administration in insulin-treated and in insulin-deprived BB rats. When compared to sodium orthovanadate, peroxovanadium compounds exhibited a markedly greater potency on a molar basis, and in relation to their toxicity. The in vivo potency can be predicted by the degree of phosphotyrosine phosphatase inhibition observed in vitro. These are the first agents other than insulin that can acutely and markedly reduce plasma glucose in hypoinsulinemic diabetic BB rats.

Key words

vanadate peroxovanadium compounds BB rats hypoglycemic agents 







insulin receptor kinase


phosphotyrosine phosphatase


body weight








Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Tolman EL, Barns E, Burns M, Pansini A, Partridge R: Effects of vanadium on glucose metabolism in vitro. Life Sciences 25:1159–1164, 1979PubMedCrossRefGoogle Scholar
  2. 2.
    Dubyak GR, KleinzellerA: The insulin-mimetic effects of vanadate in isolated rat adipocytes. J Biol Chem 255: 5306–5312, 1980PubMedGoogle Scholar
  3. 3.
    Schechter Y, Karlish S JD: Insulin-like stimulation of glucose oxidation in rat adipocytes by vanadyl (iv) ions. Nature (Lond) 284:556–558, 1980CrossRefGoogle Scholar
  4. 4.
    Degani H, Gochin M, Karlish SJD, Shechter Y: Electron paramagnetic resonance studies and insulin-like effects of vanadium in rat adipocytes. Biochemistry 20: 5795–5799, 1989CrossRefGoogle Scholar
  5. 5.
    Duckworth WC, Solomon SS, Liepnieks J, Hamel FG, Hand S, Peavy DE: Insulin-like effects of vanadate in isolated rat adipocytes. Endocrinology 122: 2285–2289, 1988PubMedCrossRefGoogle Scholar
  6. 6.
    Mooney RA, Bordwell KL, Luhowskyj S, Casnellie JE: The insulin-like effect of vanadate on lipolysis in rat adipocytes is not accompanied by an insulin-like effect on tyrosine phosphorylation. Endocrinology 124: 422–429, 1989PubMedCrossRefGoogle Scholar
  7. 7.
    Clark AS, Fagan JM, Mitch WE: Selectivity of the insulin-like actions of vanadate on glucose and protein metabolism in skeletal muscle. Biohem J: 232: 273–276, 1975Google Scholar
  8. 8.
    Heylinger CE, Tahiliani AG, McNeill JH: Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats. Science 277: 1474–1477, 1985CrossRefGoogle Scholar
  9. 9.
    Gil J, Miralprix M, Carreras J, Bartrons R: Insulin-like effects of vanadate on glucokinase activity and fructose 2, 6-biphosphate levels in the liver of diabetic rats. J Biol Chem 263: 1868–1871, 1988PubMedGoogle Scholar
  10. 10.
    Blondel O, Bailbe D, Portha B: In vivo insulin resistance in strepto-zotocin-diabetic rats-evidence for reversal following oral vanadate treatment. Diabetologia 32: 185–190, 1989PubMedCrossRefGoogle Scholar
  11. 11.
    Bendayan M, Gingras D: Effects of vanadate administration on blood glucose and insulin levels as well as on the exocrine pancreatic function in streptozotocin-diabetic rats. Diabetologia 32: 561–567, 1989PubMedCrossRefGoogle Scholar
  12. 12.
    Ramanadham S, Mongold JJ, Brownsey RW, Cros GH, McNeill JH: Oral vanadyl sulphate in treatment of diabetes mellitus in rats. Am J Physiol 257: H904–H911, 1989PubMedGoogle Scholar
  13. 13.
    Pugazhenti S, Khandelwal RL: Insulinlike effects of vanadate on hepatic glycogen metabolism in nondiabetic and streptozotocin-induced diabetic rats. Diabetes 39: 821–827, 1990CrossRefGoogle Scholar
  14. 14.
    Meyerovitch J, Farfel Z, Sack J, Shechter Y: Oral administration of vanadate normalizes blood glucose levels in streptozotocin-treated rats. J Biol Chem262: 6658–6662, 1987Google Scholar
  15. 15.
    Brichard SM, Okitolonda W, Henquin JC: Long term improvement of glucose homeostasis by vanadate treatment in diabetic rats. Endocrinology 123: 2048–2053, 1988PubMedCrossRefGoogle Scholar
  16. 16.
    Pederson RA, Ramanadham S, Buchan AMJ, McNeill J: Long-term effects of vanadyl treatment on streptozotocin-induced diabetes in rats. Diabetes 38: 1390–1395, 1989PubMedCrossRefGoogle Scholar
  17. 17.
    Bollen M, Miralpeix M, Ventura F, Toth B, Bartrons R, Stalmans W: Oral administration of vanadate to streptozotocin-diabetic rats restores the glucose-induced activation of liver glycogen synthase. Biochem J 267: 269–271, 1990PubMedGoogle Scholar
  18. 18.
    Sakurai H, Tsuchiya K, Nukatsuka M, Sofue M, Kawada J: Insulin-like effects of vanadyl ion on streptozotocin-induced diabetic rats. J of Endocrinol 126:451–459, 1990CrossRefGoogle Scholar
  19. 19.
    Serradas P, Bailbe D, Blondel O, Portha B: Abnormal b-cell function in rats with non-insulin-dependent diabetes induced by neonatal strepto-zotocin: effect of in vivo insulin, phlorizin, or vanadate treatments. Pancreas 6: 54–62, 1991PubMedCrossRefGoogle Scholar
  20. 20.
    Ramanadham S, Brownsey RW, Cros GH, Mongold JJ, McNeill JH: Sustained prevention of myocardial and metabolic abnormalities in diabetic rats following withdrawal from oral vanadyl treatment. Metabolism 38: 1022–1028, 1989PubMedCrossRefGoogle Scholar
  21. 21.
    Domingo JL, Gomez M, Llobet JM, Corbella J, Keen CL: Improvement of glucose homeostasis by oral vanadyl or vanadate treatment in diabetic rats is accompanied by negative side effects. Pharmacology and Toxicology 68: 249–253, 1991PubMedCrossRefGoogle Scholar
  22. 22.
    Domingo JL, Gomez M, Llobet JM, Corbella J, Keen CL: Oral vanadium administration to streptozotocin-diabetic rats has marked negative side-effects which are independent of the form of vanadium used. Toxicology 66: 279–287, 1991PubMedCrossRefGoogle Scholar
  23. 23.
    Valera A, Rodriguez-Gil JE, Bosch F: Vanadate Treatment Restores the Expression of Genes for Key Enzymes in the Glucose and Ketone Bodies Metabolism in the Liver of Diabetic Rats. J Clin Invest 92: 4–11, 1993PubMedCrossRefGoogle Scholar
  24. 24.
    Oster MH, Llobet JM, Domingo JL, Gedrman JB, Keen CL: Vanadium treatment of diabetic Sprague-Dawley rats results in tissue vanadium accumulation and pro-oxidant effects. Toxicology 83: 115–130, 1993PubMedCrossRefGoogle Scholar
  25. 25.
    Madsen KL, Porter VM, Fedorak RN: Oral vanadate reduces Na(+)-dependent glucose transport in rat small intestine. Diabetes 42:1126–32, 1993PubMedCrossRefGoogle Scholar
  26. 26.
    Venkatesan N, AvidanA, Davidson MB: Antidiabetic Action of Vanadyl in rats independent of in vivo insulin-receptor kinase activity. Diabetes 40: 492–498, 1991PubMedCrossRefGoogle Scholar
  27. 27.
    Thompson KH, Leichter J, McNeill JH: Studies of Vanadyl Sulfate as a Glucose-Lowering Agent in STZ-Diabetic rats. Biochem and Biophys Research Comm 197: 1549–1555, 1993CrossRefGoogle Scholar
  28. 28.
    Bollen M, Miralpeix M, Ventura F, Toth B, Bartrons R, Stalmans W: Oral administration of vanadate to streptozotocin-diabetic rats restores the glucose-induced activation of liver glycogen synthase. Biochem J 267: 269–271, 1990PubMedGoogle Scholar
  29. 29.
    Malabu UH, Dryden S, McCarthy HD, KilpatrickA, Williams G: Effects of chronic vanadate administration in the STZ-induced diabetic rat: the antihyperglycemic action of vanadate is attributable entirely to its suppression of feeding. Diabetes 43:9–15, 1994PubMedCrossRefGoogle Scholar
  30. 30.
    Sekar N, Kanthasany A, William S, Subramanian S, Govindasamy S: Insulin actions of vanadate in diabetic rats. Pharmacological Research 22: 207–217, 1989CrossRefGoogle Scholar
  31. 31.
    Mongold JJ, Cros GH, Vian L, Tep A, Ramanadham S, Siou G, Diaz J, McNeill JH, Serrano J J: Toxicological Aspects of Vanadyl Sulphate on Diabetic Rats: Effects on Vanadium Levelsand Pancreatic b-Cell Morphology. Pharmacology and Toxicology 67: 192—198, 1990Google Scholar
  32. 32.
    Cam MC, Pederson RA, Brownsey RW, McNeill JH: Long-term effectiveness of oral vanadyl sulphate in streptozotocin-diabetic rats. Diabetologia 36: 218–224, 1993PubMedCrossRefGoogle Scholar
  33. 33.
    Rossetti L, Laughlin MR: Correction of chronic hyperglycemia with vanadate, but not with phlorizin, normalizes in vivo glycogen repletion and in vitro glycogen synthase activity in diabetic skeletal muscle. J Clin Invest 84: 892–899, 1989PubMedCrossRefGoogle Scholar
  34. 34.
    Rossetti L, Giaccari A, Klein-Robbenhaar E, Vogel LR: Insulinomimetic properties of trace elements and characterization of their in vivo mode of action. Diabetes 39: 1243–1250, 1990PubMedCrossRefGoogle Scholar
  35. 35.
    Ramanadham S, Cros GH, Mongold JJ, Serrano JJ, McNeill JH: Enhanced in vivo sensitivity of vanadyl-treated diabetic rats to insulin. Can J Physiol Pharmacol 68: 486–491, 1990PubMedCrossRefGoogle Scholar
  36. 36.
    Battell ML, Yuen VG, McNeill JH: Treatment of BB rats with vanadyl sulphate. Pharmacology Communications 1:291–301, 1992Google Scholar
  37. 37.
    Brichard SM, Pottier AM, Henquin JC: Long term improvement of glucose homeostasis by vanadate in obese hyperinsulinemic fa/fa rats. Endocrinology 125: 2510–2516, 1989PubMedCrossRefGoogle Scholar
  38. 38.
    Meyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir S, Kahn CR: Vanadate normalizes hyperglycemia in two mouse models of non-insulin-dependent diabetes mellitus. J Clin Inv 87: 1286–1294, 1991CrossRefGoogle Scholar
  39. 39.
    Brichard SM, Bailey CJ, Henquin JC: Marked improvement of glucose homeostasis in diabetic ob/ob mice given oral vanadate. Diabetes 39: 1326–1332, 1990PubMedCrossRefGoogle Scholar
  40. 40.
    Kadota S, Fantus IG, Deragon G, Guyda HJ, Posner BI: Stimulation of insulin-like growth factor II receptor binding and insulin receptor kinase activity in rat adipocytes. J Biol Chem 262: 8252-S256, 1987PubMedGoogle Scholar
  41. 41.
    Fantus IG, Kadota S, Deragon G, Foster B, Posner BI: Pervanadàte (peroxide(s) of vanadate) mimics insulin action in rat adipocytes via activation of the insulin-receptor tyrosine kinase. Biochemistry 28: 8864–8871, 1989PubMedCrossRefGoogle Scholar
  42. 42.
    Faure R, Baquiran G, Bergeron JJM, Posner BI: The dephosphorylation of insulin and epidermal growth factor receptors. J Biol Chem 267: 11215–11221, 1992PubMedGoogle Scholar
  43. 43.
    Posner BI, Faure R, Burgess JW, Bevan AP, Lachance D, Zhang-Sun G, Fantus IG, Ng JB, Hall DA, Soo Lum B, Shaver A: Peroxo-vanadium compounds: A new class of potent phosphotyrosine phosphatase inhibitors which are insulin mimetics. J Biol Chem 269: 4596–4604, 1994PubMedGoogle Scholar
  44. 44.
    Cros G, Mongold JJ, Serrano JJ, Ramanadham S, McNeill JH: Effects of vanadyl derivatives on animal models of diabetes. Molecular and Cellular Biochemistry 109: 163–166, 1992PubMedGoogle Scholar
  45. 45.
    Chicheportiche D, Darquy S, Lepeintre J, Khosrovani C, Rouchette J, Capron F, Halban P, Reach G: Implantation d’îlots de porc microen-capsulés chez le rat diabétique. Dîabète et Métabolisme 15: IV, 1989 (abstract)Google Scholar
  46. 46.
    Obih P, Wingard M, Olubadewo J. Effectiveness of alzet minipump administration of vanadyl sulphate in prevention of STZ-induced diabetes. FASEB J 6: A1591, 1992 (abstract)Google Scholar
  47. 47.
    Yale JF, Grose M, Marliss EB: Pathogenesis of the Type I Diabetes Mellitus of the BB Rat. In: F. Labrie and L. Proulx (eds). Endocrinology, Exerpta Medical International Congress Series #655, Amsterdam, pp 89–91, 1984Google Scholar
  48. 48.
    Kadota S, Fantus IG, Deragon G, Guyda HJ, Hersh B, Posner BI: Peroxide(s) of vanadium: a novel and potent insulin-mimetic agent which activates the insulin receptor kinase. Biochem. Biophys Res Comm 147: 259–266, 1987PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • J. F. Yale
    • 1
  • C. Vigeant
    • 1
  • C. Nardolillo
    • 1
  • Q. Chu
    • 1
  • J.-Z. Yu
    • 1
  • A. Shaver
    • 2
  • B. L. Posner
    • 3
  1. 1.McGill Nutrition and Food Science CentreRoyal Victorial HospitalMontrealCanada
  2. 2.Department of ChemistryMcGill UniversityMontrealCanada
  3. 3.Polypeptide Hormone LaboratoryMcGill UniversityMontrealCanada

Personalised recommendations